This invention relates to the syntheses of certain new dinuclear platinum complexes as cisplatin analogs and the use of these cisplatin analogs to treat cancer.
Cisplatin (cis-diamminedichloroplatinum, cis-Pt(NH.sub.3).sub.2 Cl.sub.2, molecular weight 300.05) has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et. al. (Nature, 1965, 205, 698; Nature, 1972, 222, 385).
Chemical & Engineering News (Oct. 23, 1995) reported that "Cisplatin was first synthesized in the 1800s, but its anticancer activity was not discovered until the 1960s. In 1979, it was approved by the Food and Drug Administration for clinical treatment of testicular and ovarian tumors and cancers of the head and neck. Cisplatin and an analog, carboplatin, are now among the most widely used anticancer drugs."
The Physician's Desk Reference reports that cisplatin (the commercial name is Platinol.RTM.) can be used to treat testicular cancer, ovarian cancer, and bladder cancer. Rosenberg et al., U.S. Pat. No. 4,177,263, describes methods of treating cancer using cisplatin and cisplatin analogs. The compound was shown to be effective for treating leukemia and tumors induced in mice.
After so many years, cisplatin is still being widely used because of its efficacy. However, its critical drawback, the toxicity, is still a major concern. Many attempts have been made to either reduce its toxicity or increase its efficacy.
Predominantly, cisplatin binds onto deoxyguanosine of DNA. It also binds onto other deoxynucleosides or nucleosides. Because of the non-selectivity of cisplatin between cancer cells and normal cells, cisplatin has a lot of side effects. Besides, cisplatin is effective only to certain kinds of cancers. Therefore, reducing the toxicity of cisplatin and expanding its use in more cancers have been very important issues for all scientists involved in its research.
Many people have attempted to change the ligand on platinum to make new cisplatin analogs in order to reduce the toxicity or improve the efficacy. Examples are made by K. C. Tsou, et al.(J. Clin. Hemat. Oncol. 1977, 7, 322,), R. J. Speeder et al. (J Clin. Hemat. Oncol. 1977,. 7, 210), A. Mathew et. al. (Chem. Comm. 1979, 222), D. Rose, et al. (Cancer Treatment Reviews, 1985, 12, 1), and D. Alberts et al. (Cancer Treatment Reviews, 1985, 12, 83).
Recently, a new type of cisplatin analogs, dinuclear platinum (II) complexes, was reported by Farrell etc. (Biochemistry, 1995, 34, 15480). Farrell prepared complexes in which cisplatin was bound to the ligand by only a single Pt--N bond. All of the complexes made by Farrell had an overall charge of +2 for the cation. The examples of Farrell's complexes are [{trans-PtCl(NH.sub.3).sub.2 }H.sub.2 N(CH.sub.2).sub.4 NH.sub.2 {trans-PtCl(NH.sub.3).sub.2 }].sup.2+, [{cis-PtCl(NH.sub.3).sub.2 }H.sub.2 N(CH.sub.2).sub.4 NH.sub.2 {cis-PtCl(NH.sub.3).sub.2 }].sup.2+, and [{trans-PtCl(py).sub.2 }H.sub.2 N(CH.sub.2).sub.4 NH.sub.2 {trans-PtCl(py).sub.2 }].sup.2+ where py is pyridine. The biological data for these complexes indicated that they may have higher efficacy or better specificity than cisplatin.